Phenotypic Expression of CFH Rare Variants in Age-Related Macular Degeneration Patients in the Coimbra Eye Study

Abstract

Purpose To determine the association between rare genetic variants in complement factor H ( CFH ) and phenotypic features in age-related macular degeneration (AMD) patients from the Coimbra Eye Study (CES). Methods AMD patients from the Incidence CES (NCT02748824) underwent ophthalmologic examination and color fundus photography, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence, and near-infrared imaging. Multimodal phenotypic characterization was carried out in a centralized reading center. The coding and splice-site regions of the CFH gene were sequenced through single-molecule molecular inversion probe–based next-generation sequencing in association with the EYE-RISK consortium. Variants with minor allele frequency <0.05 resulting in splice-site or protein change were selected. Differences in phenotypic features between carriers and noncarriers were analyzed using generalized estimated equations logistic regression models, considering intereye correlations. Results We included 39 eyes of 23 patients carrying rare CFH variants and 284 eyes of 188 noncarriers. Carrier status was associated with having higher drusen burden in the macula in the inner Early Treatment Diabetic Retinopathy Study circle (odds ratio [OR], 5.44 [95% confidence interval {CI}, 1.61–18.37]; P = 0.006), outer circle (OR, 4.37 [95% CI, 1.07–17.77]; P = 0.04), and full grid (OR, 4.82 [95% CI, 1.13–20.52]; P = 0.033). In SD-OCT, a lower total macular volume and lower inner retinal layers’ volume (OR, 0.449 [95% CI, 0.226–0.894]; P = 0.023; OR, 0.496 [95% CI, 0.252–0.979]; P = 0.043) and pigment epithelial detachments (PEDs) (OR, 5.24 [95% CI, 1.08–25.44]; P = 0.04) were associated with carrying a rare CFH variant. Carriers with subretinal drusenoid deposits (SDD) had the rare variant P258L in all cases except one. Conclusions We identified in our cohort phenotypic differences between carriers and noncarriers of rare variants in the CFH gene. Carriers had more severe disease, namely superior drusen burden, PEDs, and thinner retinas. The rare variant P258L may be associated with SDD. Carriers are probably at increased risk of progression.

Age-Related Macular Degeneration and Extramacular Drusen: Genetic Associations in the Coimbra Eye Study

“…5,6,9 Plus, in this GWAS, a significant burden of rare variants was observed in the CFH and CFI genes, and others confirmed that rare variants conferred a high risk of disease and were associated with a more severe phenotype, including widespread extramacular drusen deposition. 5,[10][11][12][13][14] In AMD, most genotype-phenotype associations performed to date rely only on the phenotypic analysis of the macular area, with few studies considering extramacular features such as drusen and pigmentary changes. 15,16 Some, however, found that these features are frequently seen in eyes with AMD and are more prevalent with increasing drusen burden in the macula, but their relevance for the development and severity of AMD is not fully understood.…”

“…The Coimbra Eye Study (CES) is a two-visit epidemiologic population-based study on the prevalence and incidence of AMD in a Portuguese population (NCT01298674, NCT02748824), and we have previously reported on the genetics influencing AMD risk. 14,[22][23][24][25][26] The present work aims to expand our genotype-phenotype analysis by evaluating the association between the sequenced risk variants, the GRS, and the presence of extramacular drusen in subjects with and without AMD.…”